In cancer, the epigenome is aberrantly reprogrammed leading to a wide range of heritable changes in gene expression such as silencing of tumor suppressor genes (TSG) (Kelly et al., 2010, Nat. Biotechnol. 28:1069-1078). The most studied epigenetic aberrations in cancer involve DNA methylation and histone post-translational modifications. Acquisition of de novo methylation in cytosine of CpG dinucleotide at the promoter region of TSG results in stable gene silencing through direct inhibition of transcription factor binding or by recruitment of methyl-binding domain (MBD) proteins such as MeCP2 (Kelly et al., 2010, Nat. Biotechnol. 28:1069-1078; Taby and Issa, 2010, CA Cancer J. Clin. 60:376-392). These MBDs are associated with other repressor complexes including histone deacetylases (HDAC) that are responsible for global loss of histone acetylation resulting in gene silencing and heterochromatin formation (Taby and Issa, 2010, CA Cancer J. Clin. 60:376-392).
Since these epigenetic modifications are reversible, one goal of epigenetic therapy of cancer is to reverse these alterations and induce TSG reactivation leading to cancer cell differentiation and cancer cell death (Baylin and Jones, 2011, Nat. Rev. Cancer 11:726-734). Clinical efficacy of epigenetic drugs led to their approval for the treatment of hematological malignancies and occasional proof-of-principle responses can be seen in solid tumors (Taby and Issa, 2010, CA Cancer J. Clin. 60:376-392; Juergens et al., 2011, Cancer Discov. 589-607). However, treatment options are limited to a small number of epigenetic drugs approved in the clinic with two DNA methylation inhibitors (decitabine and azacitidine) and two HDAC inhibitors (vorinostat and depsipeptide). There is a need to discover new candidate epigenetic drugs, including some that work through other mechanisms of action. Drug discovery initiatives are underway in rare and specific cancer types with well-defined mutations in epigenetic effectors. However, these efforts may take years before approval and may have limited effects outside of a restricted patient population (Arrowsmith et al., 2012, Nat. Rev. Drug Discov. 11:384-400).
There is a need in the art to identify novel compounds which are useful for the treatment of cancer, in addition to other diseases and disorder, and do not cause deleterious side effects in the subject. The present invention fulfills this need.